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Microvascular dysfunction and sympathetic hyperactivity in women with supra-normal left ventricular ejection fraction (snLVEF)

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Abstract

Background

Recently, a new disease phenotype characterized by supra-normal left ventricular ejection fraction (snLVEF) has been suggested, based on large datasets demonstrating an increased all-cause mortality in individuals with an LVEF > 65%. The underlying mechanisms of this association are currently unknown.

Methods

A total of 1367 patients (352 women, mean age 63.1 ± 11.6 years) underwent clinically indicated rest/adenosine stress ECG-gated 13N-ammonia positron emission tomography (PET) between 1995 and 2017 at our institution. All patients were categorized according to LVEF. A subcohort of 698 patients (150 women) were followed for major adverse cardiac events (MACEs), a composite of cardiac death, non-fatal myocardial infarction, cardiac-related hospitalization, and revascularization.

Results

The prevalence of a snLVEF (≥ 65%) was higher in women as compared to that in men (31.3% vs 18.8%, p < 0.001). In women, a significant reduction in coronary flow reserve (CFR, p < 0.001 vs normal LVEF) and a blunted heart rate reserve (% HRR, p = 0.004 vs normal LVEF) during pharmacological stress testing—a surrogate marker for autonomic dysregulation—were associated with snLVEF. Accordingly, reduced CFR and HRR were identified as strong and independent predictors for snLVEF in women in a fully adjusted multinomial regression analysis. After a median follow-up time of 5.6 years, women with snLVEF experienced more often a MACE than women with normal (55–65%) LVEF (log rank p < 0.001), while such correlation was absent in men (log rank p = 0.76).

Conclusion

snLVEF is associated with an increased risk of MACE in women, but not in men. Microvascular dysfunction and an increased sympathetic tone in women may account for this association.

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Data availability statement

The dataset generated and analyzed during this study is available from the corresponding author on reasonable request.

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Funding

CG was supported by grants from the Swiss National Science Foundation (SNSF); the Olga Mayenfisch Foundation, Switzerland; the OPO Foundation, Switzerland; the Novartis Foundation, Switzerland; the Swiss Heart Foundation; the Helmut Horten Foundation, Switzerland; the EMDO Foundation, Switzerland; the Iten-Kohaut Foundation, Switzerland; and the University Hospital Zurich Foundation. SB was supported by the University of Zurich (UZH) Foundation.

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Authors and Affiliations

  1. Department of Nuclear Medicine, University Hospital Zurich, Raemistrasse 100, 8091, Zurich, Switzerland

    Monika Maredziak, Susan Bengs, Angela Portmann, Ahmed Haider, Winandus J. Wijnen, Geoffrey I. Warnock, Dominik Etter, Sandro Froehlich, Michael Fiechter, Alexander Meisel, Valerie Treyer, Tobias A. Fuchs, Aju P. Pazhenkottil, Ronny R. Buechel, Philipp A. Kaufmann & Catherine Gebhard

  2. Center for Molecular Cardiology, University of Zurich, Zurich, Switzerland

    Monika Maredziak, Susan Bengs, Angela Portmann, Ahmed Haider, Winandus J. Wijnen, Geoffrey I. Warnock, Dominik Etter, Sandro Froehlich, Michael Fiechter & Catherine Gebhard

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  1. Monika Maredziak
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Correspondence to Catherine Gebhard.

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Conflict of interest

All authors have the following to disclose: the University Hospital of Zurich holds a research contract with GE Healthcare. CG has received research grants from the Novartis Foundation, Switzerland.

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All procedures involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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The study was approved by the local ethics committee (BASEC No. 2017–01112). The need for informed written consent was waived by the ethics committee.

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Maredziak, M., Bengs, S., Portmann, A. et al. Microvascular dysfunction and sympathetic hyperactivity in women with supra-normal left ventricular ejection fraction (snLVEF). Eur J Nucl Med Mol Imaging 47, 3094–3106 (2020). https://doi.org/10.1007/s00259-020-04892-x

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